Biennial and Annual Report on the Rare Diseases Research Activities at the National Institutes of Health FY 2004

National Institute of Allergy and Infectious Diseases (NIAID)

Overview of Rare Diseases Research Activities

The National Institute of Allergy and Infectious Diseases (NIAID) has a long history of research support for diseases that are classified as rare and has made considerable progress from basic discoveries in microbiology and immunology to the development of diagnostics, therapeutics, and preventive measures such as vaccines. Continued progress in this area of research will have considerable impact on the future of our Nation’s public health and quality of life. NIAID supports research activities on rare diseases that are classified into four areas: infectious diseases, primary immunodeficiency diseases, autoimmune diseases, and other immune system-mediated conditions.

  • Infectious diseases are caused by bacteria, viruses, fungi, protozoans, and other parasites.
  • Primary immunodeficiency diseases are hereditary disorders caused by intrinsic defects in the cells of the immune system and are characterized by unusual susceptibility to infection.
  • Autoimmune diseases result from a dysfunction of the immune system in which the body attacks its own organs, tissues, and cells.
  • Other immune system-mediated diseases, such as asthma and allergic diseases, are characterized by immune responses that cause disease.

NIAID research on rare diseases seeks to delineate the immune mechanisms of disease pathogenesis and develop new and more effective strategies to diagnosis, treat, and prevent these diseases. Some of these diseases are considered Category A priority pathogens, which means that they pose the gravest threat should they be used as an agent of bioterror.

Recent Scientific Advances in Rare Diseases Research

Rare Infectious Diseases


Amebiasis is the third leading cause of death worldwide, according to the World Health Organization (WHO). Infection with the pathogenic protozoan Entamoeba histolytica results in acute diarrheal illness and may also lead to a chronic condition that progresses to more severe symptoms including amebic colitis and liver abscess. The parasitic amoeba adheres to intestinal cells by binding to specific cell surface proteins, called lectins. Recently, NIAID-supported investigators hypothesized that a vaccine made from this lectin may interrupt parasite adherence, thus stopping the infection and preventing disease progression. Using a mouse model, these investigators found that vaccination with either native lectin or recombinant lectin was effective in preventing intestinal infection. If proven as effective in humans, this vaccine may ultimately reduce the transmission of amebiasis and prevent complications of the invasive disease in a significant number of people.


Anthrax is an acute infectious disease caused by the spore-forming, rod-shaped bacterium Bacillus anthracis, which is considered a Category A priority pathogen. By uncovering the molecular pathways that enable the bacterium to form spores, survive in people, and cause illness, NIAID hopes to identify new ways to diagnose, prevent, and treat anthrax. In FY 2004, NIAID-funded researchers determined the three-dimensional structure of the cell-binding component of anthrax toxin, called protective antigen (PA), binding tightly to a target cell surface protein called CMG2. This finely detailed snapshot of the structure of the PA protein-CMG2 receptor complex offers insight into a crucial step in the pathway that allows anthrax toxin to enter human cells. This work provides important new leads for the development of novel antitoxins that could save lives late in the disease when large amounts of toxin are present and antibiotics are less effective.

In other research, NIAID-supported scientists discovered genes for toxins of the bacterium B. anthracis and an opportunistic pathogen, Bacillus cereus, which is known to cause food poisoning. The finding that the two species (B. anthracis and B. cereus) share genes including those that create the deadly anthrax toxin underscores the complexity of diagnosing anthrax since another species related to B. cereus causes an inhalation anthrax-like disease. This study also demonstrated that approaches such as rapid genome sequencing and analysis of clinical isolates can provide the genetic basis for an observed clinical phenotype.


Botulism is caused by neurotoxins produced by Clostridium botulinum, a Category A priority pathogen. Research supported by NIAID seeks to detect neurotoxin DNA markers since current tests cannot distinguish the organism when it is releasing toxin from when it is not. The expression of recombinant botulinum neurotoxin heavy and light chain proteins has been hindered by their extreme lack of stability and solubility. NIAID-funded investigators have made advances in overcoming these obstacles and in expressing recombinant botulinum neurotoxin light chain fragments. The availability of recombinant fragments is important to the development of high-throughput assays that can be used to screen neurotoxin inhibitors. In addition, NIAID-supported investigators have described a subtype of serotype A neurotoxin, the “so called” A2 neurotoxin gene cluster in C. botulinum. Further characterization and understanding of serotype A toxins is essential to the development of countermeasures that will be broadly protective against the neurotoxin.


The comma-shaped bacterium Vibrio cholerae causes severe diarrheal disease. Epidemics of cholera tend to follow blooms of chitin-producing zooplankton, and efforts to filter out zooplankton are protective against the disease. The basic unit of chitin is a monosaccharide, N-acetylglucosamine (GlcNAc) that acts as a chemoattractant to V. cholerae. GlcNAc induces expression of V. cholerae genes involved in its utilization by the bacterium. An NIAID-supported investigator and colleagues have described three genetic pathways encoding regulatory proteins in V. cholerae that are involved in control of chemotaxis towards GlcNAc, regulation of attachment, and utilization of chitin. The ubiquity of Vibrio species in the environment strongly suggests a major role for this genus in the recycling of insoluble planktonic chitin and, therefore, in the global oceanic carbon cycle. Environmental changes that impact plankton growth such as increased nutrient levels and temperatures in coastal regions may be predictive of emerging cholera epidemics.


Cryptococcosis, which is caused by the fungus Cryptococcus neoformans, is a life-threatening infection of the central nervous system (CNS) that commonly affects immunocompromised individuals. Cryptococcal meningoencephalitis (CM) develops as a result of inhaled C. neoformans traveling through the blood stream from the lung to the brain. Recently, NIAID-supported scientists, utilizing an animal model of CM infection, determined that the combination of a polyene [amphotericin B] with an azole [fluconazole] exhibited greater antifungal potency than amphotericin B alone, amphotericin B plus flucytosine, or fluconazole plus flucytosine. The treatment efficacy of the two-drug protocol demonstrated in this study is in sharp contrast to the clinical observation that amphotericin B and fluconazole are antagonistic when administered together. The data have contributed to the design of an international human clinical trial to address the need for more effective antifungal therapy for CM. Findings from an NIAID intramural study trace transfer of C. neoformans across the endothelial cells that form the blood brain barrier to invade the central nervous system.


Dengue epidemics, which are caused by mosquito-borne transmission of the Dengue virus, increasingly pose public health problems in most tropical and subtropical countries. Secondary infections with the virus cause a hemorrhagic form of the disease. A safe and effective live dengue vaccine is still not available. Using an alternative vaccine strategy, NIAID intramural scientists developed a live, attenuated strain of the virus—which is now undergoing phase I clinical trials. In another study, NIAID-supported researchers recently identified the role of a gene that regulates egg production in response to blood meals in the mosquito, Aedes aegypti, that carries dengue and yellow fever. This discovery may reveal new strategies for reducing the ability of this mosquito species to reproduce.

Epstein-Barr Virus

Over 90 percent of persons in the United States are infected with the Epstein-Barr virus (EBV) and recover from the infection completely. Rarely, patients never recover and have a chronic, active infection with the virus that is ultimately fatal. NIAID intramural scientists have identified mutations in the gene encoding perforin that prevented its maturation in a patient with chronic active EBV infection. Perforin is important for destruction of certain virus-infected cells and the mutation was associated with impairment in this cell activity. The scientists identified that the mutation prevents maturation of the virus in a patient with chronic active EBV infection. Better understanding of the role of perforin and related proteins may lead to improved therapies for EBV-related infections and cancers.

Escherichia Coli (Diarrheagenic)

Escherichia coli, and other microbial infections, are increasingly difficult to treat because of the emergence of drug-resistant strains. Based on previous studies, NIAID-supported investigators developed an in vitro or test tube model of the human colon. The culture system, called the intestinal simulator, is a continuous-flow anaerobic culture that is inoculated with fecal samples from healthy volunteers. The resulting environment mimics the human gastrointestinal tract in terms of pH, oxygen tension, osmolarity, etc., and can be used to cultivate enteric pathogenic bacteria such as enteroaggregative E. coli (EAEC). The expression of bacterial genes, including factors that are necessary for bacterial virulence, can be measured and studied under these conditions. Interestingly, the nature of the normal bacterial flora contained in the intestinal simulator influenced the expression of EAEC genes. The generation of such a system is important because: (1) no animal models exist for many pathogens that cause diarrhea; (2) many pathogens are host species specific; and (3) this system mimics the human intestine.


Ebola virus, a rare and deadly microbe that causes hemorrhagic fever, is characterized by high fever and massive internal bleeding. Ebola is considered a Category A priority pathogen. The first human trial of a vaccine designed to prevent Ebola infection was initiated in FY 2004 by the NIAID Vaccine Research Center (VRC). The candidate DNA vaccine is synthesized using modified, inactivated genes from Ebola virus and does not contain any infectious material. This gives the immune system information about viral structures so that it can mount a rapid defense should the real virus ever be encountered. In addition, the VRC is currently testing a fast-acting candidate Ebola vaccine. A single injection of this fast-acting, experimental Ebola vaccine successfully protected monkeys after only 1 month. In this study, VRC scientists immunized eight monkeys with a single-boost injection, consisting of attenuated adenovirus containing genes for important Ebola antigens. The monkeys were then delivered to the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), where they were injected with an Ebola virus strain obtained from a fatally infected person from the former Zaire in 1995. The single vaccine injection completely protected all eight animals against Ebola infection, even those animals receiving high doses of the virus. This finding suggests that it might be possible to quickly contain Ebola outbreaks with ring vaccination, which aims to contain an outbreak by inoculating all identified contacts of the first detected cases and contacts of contacts as well. Ultimately, VRC scientists envision a possible two-stage vaccination strategy called prime-boost: After “priming” with the DNA vaccine, the immune system response is “boosted,” or augmented, by a second inoculation with the adenoviral component. The booster essentially sets the immune system on alert against future infection by the Ebola virus.


Giardia intestinalis is a very common protozoan parasite that causes diarrhea. The disease is especially serious in developing countries, where people are frequently malnourished. Recently, scientists discovered that Giardia, which possess a nucleus, also possess small mitochondria-like organelles, which they named “mitosomes.” These mitosomes were identified using molecular genomic techniques and were then located using immunohistochemistry and electron microscopy. The presence of these organelles, which differ significantly from the mitochondria found in human cells, helps to explain why current drugs of choice are effective (e.g., metronidazole) and may form the basis for developing novel drugs and vaccines.

Histoplasmosis Capsulatum

The fungus Histoplasma capsulatum is a significant cause of potentially fatal infection in persons with weakened immune systems such as individuals with HIV/AIDS. Current therapies are often inadequate and cause liver failure or other problems that make it necessary to halt treatment. Now, NIAID-supported investigators have developed a specific antibody that protects mice from infection with H. capsulatum. This monoclonal antibody recognizes a protein on the yeast surface and directs the host’s white blood cells to engulf the fungus. While H. capsulatum normally survives in the cells that engulfed it, these cells are killed more quickly because the antibody recognizes yeast epitopes that appear on its surface. This is the first demonstration of the use of an antibody to protect against H. capsulatum infection.

Hepatitis E Virus

The identification of antibodies to Hepatitis E virus (HEV) and the mapping of their corresponding neutralization epitopes enabled NIAID intramural scientists to develop an enzyme-linked immunosorbent assay (ELISA) that specifically detects antibodies that neutralize HEV. With this tool, scientists can now evaluate results of vaccine trials and improve vaccine formulations and delivery schedules. Availability of this test should decrease the number of monkeys needed for efficacy studies and may provide insight into the natural history and clinical course of HEV.


Leishmaniasis is a parasitic disease that infects more than 12 million people on several continents, and another 400,000 people are at risk for infection. At this time, there is no effective vaccine against human cutaneous leishmaniasis. Based on results of previous studies, scientists believe that long-term immunity to Leishmania requires continued presence of the parasite; however, attempts to create attenuated (with reduced virulence) parasites that persist in the host and confer protection without reverting to a virulent state have shown limited success. Now, NIAID-supported investigators have designed a vaccine using parasites that lack a key Leishmania protein, lpg2, and administered it to mouse models that are normally susceptible to Leishmania infection. When these mice were later challenged with Leishmania major protozoa, they were protected from infection without suffering overt cutaneous lesions. Although more studies are necessary, this type of vaccine may prove to be useful in treating human disease. In addition, in an intramural study using massive cDNA sequencing, proteomics, and computational biology approaches, NIAID scientists isolated the most abundant secreted proteins from the salivary glands of the sand fly, Lutzomyia longipalpis, a Leishmania vector. Sixteen of these proteins appear to be unique to sand flies. Because of the relationship between the vertebrate host immune response to salivary proteins and protection from infection with the parasite, these proteins are promising markers for vector exposure and attractive targets for vaccine development to control Leishmania chagasi infection.

The protozoan parasite Leishmania major is transmitted through sandflies to humans, where it invades macrophages (cells that ingest and digest foreign substances) and may result in the debilitating disease known as visceral leishmaniasis. The Leishmania LACK antigen is a key target of immune response in susceptible mouse models of the disease and is being studied as a potential drug target to treat leishmaniasis. Drugs now used to treat leishmaniasis are very toxic and scientists are studying ways to improve management of the disease. In an NIAID-supported study, researchers found that, although they were able to target and select individual LACK genes in the organisms, the parasites remained attenuated, even in normally very susceptible mice. This encouraging finding supports the hypothesis that the LACK protein may be a useful target for therapeutic, if not immunologic, intervention against leishmaniasis.

NIAID intramural scientists also identified a sand fly receptor that is critical for the survival of Leishmania major in the midgut of the sand fly vector. This identification of an insect molecule central to survival and transmission of the protozoan parasite opens new avenues for studies of insect immunity, transmission-binding vaccines, and host-parasite co-evolution.

Lyme Disease

NIAID intramural scientists identified for the first time using direct molecular genetic investigation the individual genes required by the bacterium Borrelia burgdorferi, the causative agent of Lyme disease, at each stage of the natural mouse-tick infection cycle. NIAID scientists demonstrated an important developmental sequence of phenotypic changes accompanying transmission that previously was not recognized for this vector-borne bacterial pathogen. The conclusion is novel because adaptive responses of bacteria that do not undergo obvious morphological changes, such as B. burgdorferi, are generally believed to be of immediate rather than delayed utility. In another study, NIAID intramural scientists collaborated with several extramural scientists to show that the amount of antibody against C6, a protein fragment from B. burgdorferi, declines after successful antibiotic therapy of Lyme disease. These results suggest that a change in the anti-C6 antibody titer may serve as an indicator of therapy outcome for patients with Lyme disease. Further studies with more patients are needed to clarify how the test may be used in the clinical setting.


Pertussis (whooping cough) is a preventable illness in all age groups but is rarely considered or diagnosed in older children or adults. An NIAID-supported investigator and colleagues are studying the role of pertussis toxin in Bordetella pertussis infection leading to the disease pertussis. Pertussis toxin is considered to be an important factor produced by this bacterium that allows it to cause disease, but its role in the infection process has not been well studied. Using mouse infection studies, these investigators showed that the toxin inhibits immune responses, suggesting the possibility that B. pertussis infection in both children and adults may render them more susceptible to secondary infections and diseases, particularly respiratory diseases.


Plague, which is considered a Category A priority pathogen, is caused by the bacterium Yersinia pestis and is transmitted to people mainly through a flea bite. An experimental plague vaccine proved 100-percent effective when tested in a new mouse model for plague infection developed by NIAID scientists at Rocky Mountain Laboratories (RML). The scientists developed their model to mimic the natural transmission route of bubonic plague through the bites of infected fleas. The scientists will use the natural challenge model to test other plague vaccines in development. They also will try to learn how plague bacteria spread through a host after being transmitted by a flea, with hopes of developing new treatments to counteract the spread of plague in infected persons.

Q Fever

Coxiella burnetii is an obligate intracellular bacterium and the causative agent of the zoonosis Q fever. Recently, NIAID intramural scientists developed a model to study C. burnetii morphogenesis that uses a specific cell line that is synchronously infected with homogeneous small cell variants harvested from aged infected cell cultures. This experimental model to study C. burnetii development will dramatically aid future efforts to define the transcriptome and proteome of developmental forms. It will also allow a thorough assessment of the biological properties of cell forms in terms of infectivity, antibiotic sensitivity, and resistance to environmental insult.

Severe Acute Respiratory Syndrome

The severe morbidity and mortality associated with severe acute respiratory syndrome (SARS), and the concern that SARS coronovirus (SARS CoV) could reemerge, make it imperative that effective means to prevent and treat the disease are developed. To this end, NIAID scientists, grantees, and industry partners are hard at work to better understand SARS and the virus that causes it and to develop effective countermeasures against this disease. Animal models of disease are critical for the development of vaccines, immunotherapeutics, and antiviral drugs. NIAID scientists and their collaborators developed several animal models for SARS, including mouse, hamster, and non-human primate models. They also determined that the transfer of immune sera from infected mice and hamsters, which contained antibodies against SARS-CoV, protected uninfected animals from SARS infection. These observations suggest that vaccines that induce neutralizing antibodies against SARS-CoV and immunoprophylaxis or immunotherapy with anti-SARS antibodies are likely to be effective against the SARS-CoV. In other efforts to evaluate the potential of immunotherapy, NIAID-funded researchers have developed a human monoclonal antibody that reduces viral replication in mice and protects them against SARS-CoV challenge.

NIAID scientists collaborated with scientists at academic institutes and in industry to develop and evaluate the immunogenicity and efficacy of vaccines against SARS-CoV in the newly developed SARS animal models. Since it is not known what type of vaccine will be most effective against the SARS-CoV, several technologically distinct methods were initiated in parallel. NIAID researchers have developed three candidate SARS vaccines, a DNA vaccine and two live attenuated virus vaccines. Scientists in the NIAID’s VRC have tested a DNA vaccine against SARS CoV and shown that it provides protection in an animal model. This DNA encodes part of the SARS virus spike protein (which protrudes from the viral envelope and helps to bind the virus to its target cells) and protects mice from virus growth in the lungs by inducing neutralizing antibodies. A phase I clinical trial of this recombinant DNA vaccine is planned for December 2004.

The attenuated live virus vaccines were made by inserting the gene encoding the SARS-CoV spike protein into two existing vaccines, modified vaccinia Ankara (MVA), which was initially developed as a vaccine against smallpox and has an excellent safety record in humans, and a recombinant attenuated human parainfluenza virus 3 (BHPIV3), which is an experimental vaccine against HPIV3, a virus that can cause respiratory illness in children. The MVA and BHPIV3 vaccines act to transport the SARS gene into the body. The MVA/S vaccine was tested in mice and the BHPIV3/S vaccine in African green monkeys. Both experimental vaccines protected the immunized animals from infection with SARS-CoV.

Whether any of these experimental SARS vaccines will protect humans against the SARS-CoV is not yet known; similarly, it is not yet known if transfer of “passive immunity” through anti-SARS antibody administration can effectively treat or prevent human SARS. NIAID intramural and extramural researchers, in collaboration with researchers worldwide, are continuing to follow up on promising leads.


Smallpox is a disfiguring and potentially deadly infectious disease caused by the Variola major virus and is a Category A priority pathogen. Approximately 25 percent of the U.S. population cannot receive the current, licensed smallpox vaccination (Dryvax) because they are at increased risk for post-vaccine complications. MVA, a much weaker form of the same virus used to make Dryvax, was used briefly in Germany and Turkey in the 1970s as a primer before immunization with the Lister smallpox vaccine. NIAID scientists and their collaborators compared immunization with MVA and Dryvax in a monkey model. After two doses of MVA or one MVA dose followed by Dryvax, the immune response was equivalent or higher than that induced by Dryvax alone. These findings are important steps in the evaluation of MVA as a replacement vaccine or pre-vaccine for those with increased risk of severe side effects from Dryvax. In addition, NIAID intramural scientists found that MVA also protects mice with certain immune deficiencies, indicating that MVA may be a promising alternative to Dryvax in humans who are partially immunodeficient.

The A28L gene of vaccinia virus is conserved in all poxviruses and encodes a protein that is anchored to the surface of infectious intracellular mature virions (IMV) and consequently lies beneath the additional envelope of extracellular virions. In an NIAID-supported study, investigators found that A28-deficient virions did not induce cytopathic effects, express early genes, or initiate a productive infection. Although A28-deficient IMV bound to the surface of cells, their cores did not penetrate into the cytoplasm. Because repression of A28 inhibited cell-to-cell spread, all forms of vaccinia virus regardless of their outer coat must use a common A28-dependent mechanism of cell penetration. Furthermore, since A28 is conserved, all poxviruses are likely to penetrate cells in a similar way. The identification of a poxvirus entry protein will facilitate the identification of additional components of the fusion complex, which will ultimately lead to an understanding of the entry process. In addition, antibodies and drugs that target A28 may be useful for vaccines and therapeutics.

Streptococcal Group A Invasive Disease

Group A streptococci (GAS) cause a wide spectrum of bacterial disease that ranges from noninvasive to life-threatening infections. NIAID-supported researchers developed a prototype vaccine that uses a recombinant protein containing protective fragments of six different M proteins. The M protein is one of the virulence factors produced by GAS. These researchers then evaluated different constructs and optimized the immune response to the vaccine. This important work has led to the first GAS vaccine clinical trial in 30 years. In addition, NIAID intramural scientists, using molecular genetic analysis combined with immunologic studies, implicated a 4-amino acid duplication in the extreme N terminus of M protein as a factor contributing to an epidemic wave of serotype M3 invasive infections. This finding has implications for GAS vaccine research. In another intramural study, NIAID scientists discovered a GAS mechanism to detect human innate host defense that triggers a pathogen survival response, in which cell wall synthesis is critical. These studies identify new potential vaccine antigens and targets for therapeutic interventions designed to control streptococcal infections.

Streptoccus Group B

Group B streptococci (GBS) cause serious bacterial illness in newborns, pregnant women, postpartum women, adults with chronic medical conditions, and the elderly. Nine serotypes of GBS have been identified, based on the capsular polysaccharide (CPS) of the bacteria. Because GBS CPS is the primary GBS virulence factor, vaccine development efforts have been focused on using GBS CPS to protect individuals from GBS disease. An effective vaccine will need to include the more virulent serotypes in the target population. Now, NIAID-supported researchers have developed an alternative method for GBS serotyping using techniques that do not require preparation of antisera. The new method was shown to be sensitive and specific when tested with GBS strains of all serotypes; it was also shown to be suitable for monitoring GBS isolates and could be applied in future epidemiologic studies to help in the development of GBS vaccines.

Streptococcus Pnemoniae, Drug-resistant Invasive Disease

From 2001 to 2004, levels of antibiotic resistance among pneumococci have remained relatively stable in adults, despite efforts at the national and local levels to reduce antibiotic overuse and promote greater use of new pneumococccal vaccine strategies. A new pediatric pneumococcal conjugate vaccine that has been shown to reduce carriage of specific serotypes of pneumococci in children was introduced in 2000. Use of the vaccine in children has been predicted to reduce rates of adult disease by reducing the reservoir of bacteria in children. Researchers have shown that levels of pneumococcal infection in adults due to serotypes contained in the new pediatric vaccine have dramatically declined over the last 3 years. To investigate this phenomenon further, NIAID-supported scientists developed a survey of adults to assess levels of pneumococcal vaccination of children in the home, where it appears likely that serotype replacement is leading to an increase in infection with nonpediatric pneumococcal serotypes in adults. While further work is needed to confirm these findings, the results suggest that future global vaccine strategies will need to consider more strategic methods for targeting at-risk groups to preserve the efficacy of the existing vaccines as well as continued efforts to develop novel pneumococcal vaccines.

Tickborne Encephalitis Virus

One potential treatment for tickborne encephalitis virus (TBE) infection in humans is the administration of recombinant interferons. NIAID intramural scientists examined the JAK-STAT signal transduction pathway in TBE virus-infected cells following stimulation with interferon and found that virus infection of various cell lines and primary dendritic cells resulted in an inhibition of the phosphorylation of STAT1 and STAT2, a critical event for interferon responses. Dendritic cells are likely to be the first cell infected by TBE viruses and orchestrate the immune responses to virus infection. As phosphorylation of STAT1 is required for dendritic cell maturation, this work provides the first evidence of immune suppression by a flavivirus.


Infection with the common protozoan parasite, Toxoplasma gondii, causes a range of symptoms from asymptomatic chronic illness to mental retardation, retinal disease, and fatal brain infection. NIAID-supported investigators are studying the immune response to T. gondii to better characterize the basis for resistance to infection. NIAID-supported investigators demonstrated that mice lacking the gene for a factor involved in gene expression, STATl, were unable to control parasite replication and rapidly succumbed to the infection. By analyzing data from this study, these investigators showed that during toxoplasmosis the major role of STAT1 is not in the development of protective responses by immune system cells called T cells, but, rather in the development of other antimicrobial mechanisms. These results help elucidate the critical immunoregulatory effects of interferon-gamma (IFN-γ) in infections by intracellular pathogens and will improve the chances for development of anti-toxoplasma vaccines and drugs.

Transmissible Spongiform Encephalopathies

Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases such as scrapie of sheep, Creutzfeldt-Jakob disease (CJD) of humans, bovine spongiform encephalopathy ("mad cow" disease), and chronic wasting disease (CWD) of deer and elk. TSEs are caused by accumulation of prion protein, an abnormal form of a protein found in humans and animals. Normal prion protein is expressed in a wide variety of tissues, yet conversion of normal prion protein to the TSE form appears to be restricted primarily to cells of the nervous and lymphoid systems. In order to determine why some cell types are more resistant to TSE infection than others, NIAID scientists developed a tissue culture system that allows them to monitor both acute and persistent abnormal prion protein (or PrP-res) formation. They demonstrated that, while any cell type can make new PrP-res following exposure to TSE infectivity, only some cell types go on to become chronically infected and make PrP-res persistently. This suggests that there are cell-specific factors that determine the susceptibility of a cell to chronic TSE infection. These factors, once identified, could be useful in designing effective anti-TSE therapeutics.

West Nile Virus

Over the past 3 years, NIAID has supported the preclinical development of a live, attenuated recombinant vaccine for West Nile virus (WNV). This vaccine was created by replacing several genes of the well-established yellow fever 17D vaccine virus with those of WNV. Preclinical testing of this WNV vaccine candidate (ChimeriVax-West Nile) has demonstrated safety, efficacy, and protection against disease in animal models (mice and non-human primates). Further development of this vaccine candidate, including phase I clinical trials in healthy adults, is under way. In addition, NIAID intramural scientists have developed two chimeric WNV vaccine candidates and one DNA vaccine candidate that have shown promising results in animal models. Despite the high level of attenuation, the chimeric vaccines induced moderate to high titers of neutralizing antibodies in monkeys and horses and prevented viremia in monkeys challenged with WNV. An Investigational New Drug application has been submitted to the Food and Drug Administration for the most attenuated of these two candidates.

The NIAID’s VRC has developed a candidate vaccine for WNV using a codon-modified gene-based DNA plasmid vaccine platform to make DNA constructs that express WNV proteins. These vaccine constructs have undergone immunogenicity testing and viral challenge studies in mice. The VRC in collaboration with Vical, Inc., has completed GMP production of the vaccine for a phase I trial scheduled for early 2005.

NIAID-supported extramural scientists, using cryo-electron microscopy and image reconstruction techniques, were able to determine the strain of WNV responsible for the outbreak in the United States. Work is under way to increase resolution and obtain structures with more detail. Such detailed visualization and characterization of viral structure is expected to lead to the rational development of antivirals by identifying critical drug or antibody target sites that could disable virus infection or replication. In addition, recent studies from NIAID-supported investigators have produced the first high-resolution three-dimensional structure of an important functional domain of the WNV envelope protein. The envelope protein is the major surface protein of the virus and plays a central role in virus attachment and entry into cells. The envelope is also the primary target of protective host immunity against WNV infection. Determination of the WNV envelope protein structure may be useful in the identification of potential targets for the development of structure-based antiviral agents, immune-based therapeutics, or vaccines.

Rare Primary Immunodeficiency Diseases

DiGeorge Syndrome

Complete DiGeorge syndrome is a rare, fatal disorder resulting from congenital absence of the thymus, the organ responsible for the development of immune cells called T cells. Patients with this disease are profoundly immunodeficient. NIAID-supported researchers have previously shown that thymus transplantation is an effective therapy for this condition. These same researchers have now undertaken thymus transplantation in infants who have small numbers of functioning T cells prior to transplantation. Because there was no tissue matching between the donors and recipients, and even small numbers of T cells increase the risk of graft rejection, these patients were immunosuppressed with T-cell depleting agents prior to transplantation. The use of T-cell depleting agents in other patient populations (e.g., kidney transplant recipients and cancer patients) has been associated with prolonged depression of T-cell counts lasting up to 1 year. In contrast, infants receiving a thymus transplant following T-cell depletion showed a return to baseline (subnormal) T-cell levels within 2 to 4 weeks, and within 6 to 7 months, the infants’ immune systems achieved the same low-normal numbers of T cells as found in adults. Tests of T-cell function at the end of 1 year showed normal or greatly improved results as compared with the pretransplant period. These results demonstrate that host T cells can proliferate and mature in a nonmatched donor thymus, even after the use of T-cell depleting agents, and may have important implications for patients who require T-cell depleting therapies for a variety of diseases.

Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is an inherited disorder caused by a defect in an enzyme called phagocyte NADPH oxidase, or phox. Individuals stricken with CGD are prone to frequent, severe bacterial and fungal infections. In a study to assess the long-term clinical safety and efficacy of IFN-γ therapy, NIAID intramural scientists followed patients for up to 9 years and showed that long-term interferon prophylaxis is effective and well tolerated in patients with CGD.

Autoimmune Diseases

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a potentially life-threatening autoimmune disease in which the body attacks its own tissues and can harm the kidneys, lungs, central nervous system, and heart. Because autoantibodies are central to this damage, scientists believe that their development coincides with or precedes clinical disease. However, little is known about the autoimmune history of patients before SLE is clinically diagnosed. Recently, an NIAID-supported investigator and colleagues showed that clinical manifestations of SLE are preceded by autoimmune changes that are under way—and continue to progress—for many years before diagnosis. The study also provides a firm basis for the concept of using autoantibodies to diagnose lupus earlier, before symptoms appear, thereby enabling clinicians to offer treatment earlier in the disease course and improve treatment outcome.

An inflammatory mediator is crucial to the abnormal longevity of SLE T cells. Self-reactive antibodies are a hallmark of SLE, a prototypic and potentially fatal autoimmune disease that disproportionately affects women in their childbearing years. Production of these antibodies is driven by autoreactive T cells that are normally eliminated but persist in SLE patients. NIAID-supported investigators determined that comparison of the activities of thousands of genes in the T cells of SLE patients and normal controls showed that stimulatory conditions that caused normal T cells to be eliminated instead caused SLE T cells to increase their expression of cyclooxygenase-2 (COX-2) and survive. Moreover, inhibiting COX-2 activity abrogated the resistance of SLE T cells. The increased COX-2 was specific to SLE T cells and did not occur in T cells from other autoimmune diseases or cancer cells. Certain COX-2 inhibitors but not others were able to restore normal responses to SLE T cells, providing a rational basis for the use of these drugs for therapy and suggesting approaches to designing more potent and specific therapeutic drugs for use in SLE.

Wegener’s Granulomatosis

Wegener’s granulomatosis (WG) is an autoimmune disease that is characterized by the formation of chronic inflammatory lesions in blood vessels, resulting in vasculitis. Although this is a systemic disorder, it typically involves the lungs and upper respiratory tract. The cause of this disease is not yet known; however, it is believed that the inflammation results from the development of antibodies to proteins in the white blood cells that fight infection. Daily cyclophosphamide (CYC) and glucocorticoids have been found to be a highly effective treatment for WG. Unfortunately, long-term follow-up of patients treated with this regimen has shown that disease relapse is common and prolonged use of CYC can result in substantial long-term toxicity. For these reasons, NIAID intramural scientists have continued to search for less toxic yet efficacious treatment approaches that would be applicable to a wide range of patients. Mycophenolate mofetil (MMF) is an immunosuppressive agent currently used to prevent solid organ transplant rejection. MMF blocks the de novo purine synthesis in a pathway critical to normal function by white immune cells called lymphocytes. In a clinical study, MMF was well tolerated and no patients had to be withdrawn as a result of medication toxicity. MMF for remission maintenance was well tolerated and may represent a less toxic alternative to CYC for remission maintenance therapy in patients with WG.

Other Rare Immune-mediated Conditions

Graft-versus-host Disease

Chronic graft-versus-host disease (cGVHD) is the most common late complication of allogeneic bone marrow or peripheral blood stem cell transplantation and remains a significant barrier to more extensive application of transplantation in the treatment of cancers or blood disorders resulting from inherited immune deficiencies. In FY 2004, NIAID intramural scientists revealed that severe cGVHD is characterized by a phenotypic imbalance of a specific subset of T cells and showed that success in treating cGVHD is associated with progressive normalization of this imbalance. Thus, monitoring this subset of T cells may provide an important diagnostic tool to aid in the evaluation of new therapies to prevent or treat cGVHD.

NIAID-supported researchers discovered that a genetic variant of the interleukin 10 (IL-10) gene decreases the risk of acute GVHD and death after hematopoietic cell transplantation (HCT) by close to 50 percent. These findings provide avenues for development of novel IL10-based therapies to decrease GVHD and mortality in patients undergoing HCT and may help clinicians better inform their patients about relative risks of HCT. In another study, an NIAID-supported investigator developed an in vitro method for robust expansion of a specific type of immune cell called the T-regulatory cells (Treg) and confirmed that these cells retain their immunomodulatory activity as evidenced by their ability to reverse new onset and chronic diabetes in a mouse model of type 1 diabetes and to prevent islet graft rejection in the diabetic mice. Most significantly, only very small numbers of Tregs specifically reactive to a self-protein in autoimmune diabetes are needed to accomplish this reversal of disease. Expansion of Tregs will allow further study of their characteristics, mechanisms of action, and application to other models of immune-mediated diseases such as graft rejection and GVHD. Ultimately, in vitro Treg expansion and reinfusion into patients may be used to treat a variety of immune-mediated diseases.

Hypereosinophilic Syndrome

Hypereosinophilic syndrome (HES) is a rare and potentially fatal disorder. NIAID intramural scientists recently described a subset of patients with a myeloproliferative variant of hypereosinophilic syndrome (MHES) characterized by elevated serum tryptase levels, increased atypical mast cells in the bone marrow, tissue fibrosis, and the presence of a genetic abnormality in which two usually discrete genes are fused together causing an increase in activity of a particular enzyme. These scientists demonstrated that imatinib mesylate is effective and well tolerated in patients with MHES. Furthermore, the dramatic clinical and hematologic response to imatinib mesylate with molecular remission demonstrates that disease eradication may be an achievable goal. The dramatic resolution of myelofibrosis seen in patients with MHES treated with imatinib mesylate in the setting of a defined molecular defect also provides a unique opportunity to investigate the pathogenesis of the fibrotic response in this and other subgroups of patients.

New Activities

Rare Infectious Diseases

  • Cytotoxic T-cell responses and T-helper responses appear to be critical components of immune responses to members of the flavivirus family. The Biodefense and Emerging Infections Research Resources Program has initiated the synthesis of overlapping peptide sets of five virion proteins of the WNV. The arrayed sets of 227 unique peptides will be made available to scientists conducting research on viral pathogenesis, immunological responses, and vaccine evaluation in a variety of animal models and humans.
  • A randomized, double-blind phase I clinical trial is under way to study a treatment strategy called passive immunization in which human antibodies that can bind the WNV particles are injected directly into a patient’s bloodstream. This ongoing trial was expanded from 35 sites to more than 60 sites in the United States and Canada.
  • In FY 2004, NIAID funded 28 of more than 150 grant applications requesting funding for research on SARS.
  • Through a grant supplement to the China CDC and their collaborators, NIAID initiated the development of three different SARS projects.
  • NIAID awarded 2 contracts for SARS vaccine development; 2 contracts for antiviral screening against SARS; has evaluated more than 20,000 chemicals for anti-SARS-CoV activity; and has identified more than 1,400 compounds with activity against SARS-CoV.
  • In FY2004, NIAID supported approximately 40 large-scale DNA sequencing genome projects for microbial pathogens and invertebrate vectors of infectious diseases.
  • NIAID awarded five cooperative agreements in 2004 that are focused on GAS and GBS research in response to RFA 03-028, Partnerships for Vaccines and Diagnostic Development. Three of these grants are focused on the development of a GAS vaccine; one grant is focused on development of a GBS vaccine; and one grant is focused on development of an improved GBS diagnostic.
  • Because of the increase in incidence of pertussis among neonates who are too young to have been immunized, a clinical trial began in the fall of 2004 to evaluate the safety of administering the pentavalent combination vaccine (DTaP-HepB-IPV; Pediarix) to infants at birth and 2 and 6 months of age along with other standard immunizations compared to the same pentavalent combination vaccine when given at 2, 4, and 6 months of age. Major objectives will include assessing the age-specific antibody responses following each vaccine dose and assessing T-cell and antigen presenting cell correlates of maturing immune responsiveness in neonates and young infants.
  • In 2004, NIAID issued a renewal of the Tropical Diseases Research Units program (TDRU; Three awards were made targeting cysteine proteases as antiparasitic targets and thymidylate synthase and fatty acid biosynthesis as antimalarial targets. The former project has led to the preclinical development of K777 as a possible oral treatment for Chagas’ disease.
  • In 2004, NIAID issued a renewal of the International Collaborations in Infectious Disease Research Program. The program currently involves 18 awards in 22 international sites.
  • NIAID continues support of advanced development and manufacture of an MVA vaccine for smallpox, with the intention of targeting MVA vaccine candidates that can be produced at a scale to support commercial manufacturing. Bavarian Nordic and Acambis, Inc., have played a key role in the development of MVA vaccine candidates under contracts awarded in FY 2003. In FY 2004, new contracts were awarded to these two companies to build upon their achievements, focus on the manufacture of larger quantities of vaccine, and provide for safety and immunogenicity trials of the MVA vaccine candidates.
  • NIAID continues support of advanced development and production of a recombinant protective antigen (rPA) vaccine for anthrax. In FY 2004, new contracts were awarded to Vaxgen and Avecia to build upon the companies’ achievements, supporting production, testing, and evaluation of consistency lots, including a second phase II clinical trial.
  • NIAID began construction of two integrated facilities that will include biocontainment laboratories: one on the NIH campus in Bethesda, Maryland, and one at the Rocky Mountain Laboratories in Hamilton, Montana. A third facility, which will be located in Frederick, Maryland, is planned.
  • Through the in vitro and Animal Models for Emerging Infectious Diseases and Biodefense program, NIAID is screening existing FDA-approved antimicrobials and immunomodulators for efficacy against inhalational anthrax. Five licensed antibiotics have been selected for study, with ciprofloxacin as a control. NIAID also is pursuing studies to determine whether the course of antibiotic therapy can be decreased by vaccinating subjects with the rPA vaccine candidates currently under development.
  • Through its in vitro and in vivo antiviral screening contracts, NIAID has supported the evaluation of hundreds of compounds for in vitro activity against models for hemorrhagic fever viruses such as yellow fever, Pichinde virus (a surrogate for Lassa), and Punta Toro virus (a surrogate for hantavirus). Approximately 240 compounds were screened in FY 2004.
  • Over 1,500 compounds, including most of the licensed antivirals, have been evaluated for anti-poxvirus activities in cell culture. Those compounds that show activity in vitro have been tested in animal models (approximately 40). To augment the efficacy of cidofovir and its orally active derivatives, NIAID has fostered development of compounds with a mechanism of action different from cidofovir’s via rational drug design and high-throughput screens. New targets for screens are being identified from genomic sequence information.
  • An Investigational New Drug (IND) to support the use of cidofovir as primary treatment of smallpox has also been developed. Additional protocols are being written for special populations, including children and people with renal impairment. Since there has been no release of smallpox, no one has been eligible for this protocol.
  • NIAID-supported Vaccine Treatment and Evaluation Units have developed clinical protocols to assess cidofovir as a treatment for complications related to smallpox vaccine. Cidofovir may be a viable back-up therapy after vaccine immune globulin has been indicated. Thus far, no one has needed to be enrolled in this protocol.
  • The Food and Waterborne Diseases Integrated Research Network expands the NIAID’s capacity to conduct research on food- and water-borne pathogens. Through the Microbiology and Botulism Research Unit, NIAID is funding the discovery of novel therapeutics to neutralize botulinum toxins in the blood or within the neuronal cell.
  • The NIAID Small Business Biodefense Program (PAS-02-149) was created to support the development of therapeutics, vaccines, adjuvants/immunostimulants, diagnostics, and selected resources for biodefense. NIAID awarded 39 new biodefense grants to small businesses in FY 2004.
  • NIAID awarded a contract to the Massachusetts Institute of Technology to support another Microbial Genome Sequencing Center to allow for rapid and cost-efficient production of high-quality, microbial genome sequences.

Other Rare Immune-mediated Diseases

  • NIAID, in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Heart, Lung and Blood Institute (NHLBI), established the Clinical Trials in Organ Transplantation (RFA-AI-04-003) program. This clinical consortium was established to improve the success of transplants for end-stage organ disease, e.g., end-stage renal disease (ESRD). ESRD is a frequent complication of many autoimmune diseases. The goals of the consortium are to identify genetic factors in patients that could help doctors predict transplant outcomes as well as responses to post-transplant therapy; develop diagnostic tests that enable early detection and ongoing monitoring of immune-related processes; and test the safety and effectiveness of new, less toxic immunosuppressive drugs. The consortium is comprised of three institutions: Brigham and Women's Hospital, Boston; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University; and the University of Pennsylvania, Philadelphia.
  • NIAID established the Genomics of Transplantation Cooperative Research Program (RFA-AI-04-002) to support interdisciplinary, large-scale, broad-scope genomic studies in clinical transplantation, including solid organ, tissue, and cell transplantation. The goal of the program is to understand the genetic basis of immune-mediated graft rejection and differences in transplant outcomes and to provide a rational basis for the development of more effective treatment and prevention strategies to improve long-term graft survival and provide better quality of life for transplant recipients.
  • The NIAID and NIDDK co-sponsor the Clinical Islet Transplantation Consortium (RFAs DK-04-004 and DK-04-005) program to perform studies of islet transplantation in patients with type 1 diabetes to improve treatment of this disease. This consortium will develop and implement single- and/or multi-center clinical studies, accompanied by mechanistic studies, in islet transplantation with or without accompanying kidney transplantation, for the treatment of type 1 diabetes.
  • In 2004, NIAID funded five applications in response to RFA AI-03-019, Pathogenesis of Polyomavirus Associated Nephropathy, that are focused on basic, preclinical, clinical, and epidemiological research projects on polyomavirus-associated nephropathy (PVAN). PVAN is a serious, emerging complication in kidney transplant recipients. Research in this area will promote a better understanding of latent polyomavirus reactivation and virulence; enhance our knowledge of immune responses to polyomavirus infection associated with nephropathy; improve risk assessment for polyomavirus infection in transplant recipients; and stimulate the development of preventive, diagnostic, and treatment strategies for PVAN.
  • The NIAID and the National Library of Medicine’s National Center for Biotechnology Information launched the first public database of results from clinical blood and marrow stem cell transplants involving unrelated donors. Accessible at, this centralized resource provides genetic data as well as age, gender, and ethnicity information on more than 1,300 transplant donors and recipients from around the world.

Ongoing Activities

Rare Infectious Diseases

  • NIAID continues to support invited investigator-initiated research grant applications focusing on the development of new diagnostics, prevention strategies, and treatments for toxins and pathogens listed in the NIAID Category A-C list of priority pathogens as well as the newly recognized SARS coronavirus.
  • NIAID continues to collaborate with USAMRIID under an Inter-Agency Agreement to develop vaccine strategies for Ebola and other viral hemorrhagic fevers.
  • NIAID and FDA, through an inter-agency agreement, continued to support the screening of compounds that may be effective against biodefense-related and emerging viruses, including vaccinia, cowpox, West Nile, yellow fever, and SARS, among others.
  • NIAID supports the development of SARS coronavirus vaccines through a variety of grants and contracts.
  • NIAID, in collaboration with USAMRIID and the Centers for Disease Control and Prevention (CDC), supports the in vitro screening of candidate drugs against the SARS coronavirus.
  • NIAID continued its support for the Collaborative Antiviral Study Group (CASG), which is a collaborative network comprised of 63 institutions that conducts clinical studies of therapies for viral infections. Through the CASG, NIAID supports four pediatric clinical trials aimed at treating neonatal herpes simplex virus infections, sepsis caused by a group of viruses called enteroviruses, and cytomegalovirus (CMV) infections involving the central nervous system.
  • NIAID continues to support a contract with the University of Alabama for a Respiratory Pathogens Reference Laboratory. This contract provides a resource facility with a major effort on reagent and assay development for measurement of the human immune response to targeted bacterial respiratory pathogens.
  • NIAID continues to support phase I/II trials for two different candidate vaccines for human CMV. In one of the studies for which enrollment is ongoing, a vaccine against CMV is being evaluated in post-partum CMV-seronegative women for its ability to prevent infection in these women. In another study, four live recombinant viruses are being evaluated for safety in seropositive individuals. This vaccine was well tolerated with no significant side effects in this population.
  • NIAID continues its involvement in a cooperative program with the USAMRIID to conduct mutually agreed upon research projects related to biodefense. Under this cooperative program, NIAID will provide funding to increase USAMRIID’s aerosol exposure capability and expand appropriate containment facilities to better support studies to evaluate products for biodefense in non-human primates being conducted in the adjoining animal facility. Ongoing projects include developing vaccines for viral hemorrhagic fevers using Ebola virus as a model, and (in conjunction with FDA) evaluating the efficacy of antibiotic treatment in a model of pneumonic plague in African green monkeys. In conjunction with the National Cancer Institute, the F1–V Plague vaccine manufacturing process is being developed in order to provide material for further animal testing of the vaccine in both pneumonic and bubonic models of disease.
  • NIAID continued its support of an ongoing phase III clinical trial conducted by the Adult AIDS Clinical Trials Group to determine whether the antiviral drug valganciclovir is safe and effective in preventing cytomegalovirus organ damage in HIV-infected subjects.
  • NIAID has continued its support of the Bacteriology and Mycology Biostatistical and Operations Unit and the Bacteriology and Mycology Study Group initiatives, which support clinical trials against fungal and resistant bacterial infections.
  • NIAID continues to support research on the prevention of GBS disease through a contract awarded to researchers at Brigham and Women’s Hospital. This collaborative multidisciplinary effort is focused on clinical studies in selected populations to further understand GBS infection and on studies of the host immune response.
  • Awards were made under the Partnerships for Vaccines and Diagnostic Development program, which focuses on the development of vaccines against GAS, GBS, and Helicobacter pylori.
  • For over 30 years, NIAID has supported two helminth (parasitic worm) resources that serve the research community. The Schistosome Resource Center is maintained by the Biomedical Research Institute and the Filaria Resource Center is maintained by the University of Georgia.
  • NIAID has continued to actively test new candidate compounds for efficacy against infectious complications of AIDS in culture and in animals through its anti-infective drug development contracts. These contracts have been awarded for research on several rare diseases caused by these microorganisms: Mycobacterium avium, Pneumocystis, Cryptosporidium, Cryptococcus, and Microsporidium.
  • NIAID continued its support of research into the fundamental mechanisms of TSE disease and transmission as well as the development of diagnostic tests and effective therapies.
  • NIAID has continued its support for the Pathogen Functional Genomics Resource Center at The Institute for Genomic Research (TIGR). The center was established to provide and distribute to the broader research community a wide range of genomic and related resources and technologies for the functional analysis of microbial pathogens and invertebrate vectors of infectious diseases.
  • NIAID has continued to provide support for databases of genomic and postgenomic information and analysis tools on sexually transmitted pathogens and poxviruses.
  • NIAID and the Department of Defense (DoD) are collaborating to provide for the coordinated development of a recombinant vaccine to protect against serotypes A and B of botulinum toxin. Through a Memorandum of Understanding (MOU) with DoD’s Chemical/Biological Defense Program, NIAID is advancing the development of the Army’s tularemia LVS vaccine by conducting toxicology testing and phase I clinical trials. The MOU is being extended beyond its original 2004 agreement to continue this collaboration.
  • NIAID continues to participate in a coordinated Federal effort in biodefense genomics and is a major participant in the National Inter-Agency Genomics Sciences Coordinating Committee (NIGSCC) that includes many Federal agencies. NIGSCC funded the National Academies of Sciences to convene a committee, hold a workshop, and produce a report that analyzes the scientific issues that accompany the public release of genome sequences for infectious agents with potential national security implications.
  • NIAID continues to coordinate genomic and postgenomic initiatives, including those related to biodefense, with other Federal agencies through participation in the Microbe Project, a Federal Interagency Working Group that coordinates microbial genomic activities. In addition, NIAID maintains contact with key scientists at specific agencies such as the Central Intelligence Agency (CIA), the Federal Bureau of Investigation (FBI), the FDA, the CDC, the DoD, the Department of Energy, the National Science Foundation, and the U.S. Department of Agriculture (

Rare Primary Immunodeficiency Diseases

  • NIAID, along with the National Institute of Child Health and Human Development (NICHD), continue to support the Primary Immunodeficiency Diseases Consortium. The Consortium: (l) provides leadership and mentoring; facilitates collaborations; enhances coordination of research efforts; and solicits, reviews, recommends, and makes awards for pilot or small research projects; (2) maintains and expands a primary immunodeficiency diseases registry, which provides data to the research community about the clinical characteristics and prevalence of these diseases; and (3) develops a repository of specimens from subjects with primary immunodeficiency diseases. In the first year, the Primary Immunodeficiency Consortium awarded nine pilot research proposals.

Autoimmune Diseases

  • NIAID, the NIDDK, and the NIH Office of Research on Women’s Health (ORWH) continue to co-sponsor the Autoimmunity Centers of Excellence (ACEs), a cooperative program that supports collaborative basic and clinical research on autoimmune diseases, including single-site or multisite pilot clinical trials of immunomodulatory therapies.
  • The Autoimmune Disease Prevention Centers conduct basic research on the development of new targets and approaches to prevent autoimmune diseases and to evaluate these approaches in pilot and clinical studies. The Prevention Centers are co-sponsored by NIAID, NIDDK, NICHD, ORWH, and the Juvenile Diabetes Research Foundation International (JDRF).
  • NIAID supports the Multiple Autoimmune Diseases Genetics Consortium (MADGC), a repository of genetic and clinical data and specimens from families in which two or more individuals are affected by two or more distinct autoimmune diseases. This repository provides well-characterized material for use in research aimed at identifying the genes involved in autoimmune diseases.
  • Through the Stem Cell Transplantation for Autoimmune Diseases Consortium, NIAID is supporting clinical trials to assess the efficacy of hematopoietic stem cell transplantation to treat several severe autoimmune diseases, including multiple sclerosis, SLE, and scleroderma.
  • NIAID chairs the NIH Autoimmune Diseases Coordinating Committee (ADCC). The ADCC was established in FY 1998 at the request of Congress to increase collaboration and facilitate coordination of research among NIH Institutes and Centers, other Federal agencies, and private groups interested in these diseases. The ADCC Autoimmune Diseases Research Plan, which was mandated in the Children’s Health Act of 2000 (P.L. 106-310), was presented to Congress in FY 2003.

Other Rare Immune-mediated Diseases

  • NIAID continues to support a multi-year cooperative agreement titled Systems Approaches to Innate Immunity, Inflammation, and Sepsis to a multidisciplinary team of researchers at the Scripps Research Institute. These researchers are employing a systems biology approach to create a comprehensive picture of innate immunity, an essential first line of defense against bacterial, viral, and fungal diseases.
  • NIAID, NIDDK, and JDRF co-sponsor the Immune Tolerance Network (ITN), an international consortium of scientists and clinicians dedicated to the clinical evaluation of promising tolerance induction therapies in four areas: autoimmune diseases, kidney transplantation, islet transplantation, and asthma and allergic diseases. The network is also developing assays and biomarkers to measure the induction, maintenance, and loss of immune tolerance in humans and is studying underlying mechanisms as an integral part of all clinical trials. The ITN includes basic scientists and physicians at more than 40 institutions in the United States, Canada, Europe, and Australia.
  • NIAID continues to support the Hyperaccelerated Awards for Mechanisms in Immunomodulation Trials. This initiative supports immune-based mechanistic studies associated with clinical trials of infectious disease vaccines and immunotherapies for immune-mediated diseases. Applications are abbreviated, submitted and reviewed monthly, and awarded as early as 13 weeks after submission. This program is co-sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIDDK, and the National Institute of Neurological Disorders and Stroke (NINDS).
  • NIAID, in conjunction with NIAMS, NINDS, ORWH, and the National Multiple Sclerosis Society, continues to support the Sex-based Differences in the Immune Response research initiative. Differences in the immune response of males and females have been documented, and women are more likely than men to suffer from autoimmune diseases. The cause of pregnancy-induced changes in immune-mediated diseases and differences in the rate and severity of disease are unclear. An increased understanding of the mechanisms underlying the differences in the immune response in males and females should allow more targeted approaches for the prevention and treatment of immune-mediated disease.

Rare Disease-specific Scientific Conferences, Symposia, and Meetings

  • NIAID convened an Expert Panel on Botulinum Therapeutics in February 2004 to identify the technical opportunities for development of novel post-exposure therapeutics for the botulinum neurotoxins. (
  • NIAID led an Inter-agency Working Group on Recombinant Botulinum Toxin Vaccine Formulation in February 2004. An interim report was submitted to the Office of the Assistant Secretary for Public Health and Human Services, DHHS, in March 2004.
  • A workshop was held in March 2004 to discuss prevention of GAS diseases and their sequelae with the focus on vaccine-related issues. This meeting was supported by the National Vaccine Program Office and included clinical investigators, research scientists, participants from U.S. government agencies (NIH, CDC, and FDA) and international organizations. Recommendations from the meeting focus on accelerating development of GAS vaccines and include the development of standardized protocols for surveillance, establishment of immune correlates of protection, considerations for vaccine trial design, and strategies for implementation.
  • In March 2004, NIAID held a workshop to discuss the development of NPC-1161B, a drug administered orally to treat Pneumocystis carinii pneumonia (PCP). The meeting focused on several aspects comprising the critical path for clinical development, including good manufacturing practices (GMP) production, pharmacokinetics, toxicology, and planning of phase I clinical trial protocols.
  • NIAID staff leads an Inter-agency Task Force to assess the vulnerability of specific foods to contamination with botulinum neurotoxins (March 2003 to present).
  • On April 29–30, 2004, the NIAID and the Food Allergy and Anaphylaxis Network co-sponsored the Symposium on the Definition and Management of Anaphylaxis. The meeting provided a forum for clinicians from different medical specialties to review the pathophysiology of anaphylaxis, compare the working definitions of anaphylaxis used by various clinical specialties, and discuss treatment options. The outcome of the symposium will be published for dissemination to the broader medical community and encourage ongoing dialogue that will lead to a more cohesive approach to diagnosis, prevention, and clinical management of anaphylaxis and to identification of promising directions for future research.
  • The NIAID supported a workshop, titled Hematopoietic Stem Cell Expansion and Immune Reconstitution, held on May 17, 2004. The goals of the workshop were to evaluate the present knowledge of bone marrow transplantation as well as the future therapeutic value of ex vivo expanded cells in the context of a possible medical countermeasure against radiation resulting from a terrorist attack or accidental exposure to radiation or nuclear materials.
  • On May 18–20, 2004, NIAID sponsored the 13th Annual International Centers for Tropical Diseases Research (ICTDR) Network meeting. The meeting included sessions on Progress in Tropical Vaccinology and Immunology, Epidemiology of Tropical Diseases, Progress in Pathogenesis Genetics and Genomics in Tropical Diseases, and Drug Development and Resistance.
  • In May 2004, NIAID sponsored a workshop to address research on the control of arboviral encephalitides, including WNV. Numerous specific recommendations regarding research needs for alphavirus and flavivirus biology, diagnostics, vaccines, and therapeutics were generated by the group. These recommendations will be used to plan future activities and initiatives within NIAID/NIH.
  • NIAID and the NIH Office of Rare Diseases co-sponsored the second Federation of American Societies for Experimental Biology (FASEB) Summer Research Conference on Transplantation Immunology, which was held June 19–24, 2004, in Snowmass, Colorado. A central theme of the conference was that research in this field is expected to provide a new generation of tools for selective immunotherapeutic prevention and intervention, for example in the areas of bone marrow as well as solid organ transplantation.
  • On September 14, 2004, NIAID convened a plenary meeting in Bethesda of principal investigators from grants funded under RFA AI-01-005, Sex-based Differences in the Immune Response, and representatives from the co-sponsors, including NIAID, NIAMS, NINDS, and the National Multiple Sclerosis Society. Investigators presented updates on current research and discussed resources, collaborations, and future directions.
  • NIAID sponsored a workshop on Eosinophilia-Myalgia Syndrome (EMS) on October 22, 2004. The meeting was attended by an expert panel, by members of the National Eosinophilia Myalgia Syndrome Network, and by several Federal agencies: FDA, CDC, and NIH Office of Dietary Supplements, NIAMS, and the National Institute of Environmental and Health Sciences. The meeting reviewed the epidemic of EMS in the late 1980s, summarized what has been learned, identified possible approaches to deal with future comparable epidemics, and discussed gaps in knowledge and directions for future research.
  • In October 2003, NIAID co-sponsored a meeting with the NIH Office of Rare Diseases on genomics and proteomics of rickettsial biodefense pathogens, including Rickettsia rickettsii.
  • NIAID staff meet on a quarterly basis with staff from the DoD Joint Vaccine Acquisition Program (JVAP) to discuss and coordinate cross-cutting issues related to their respective development activities of a recombinant botulinum vaccine.
  • NIAID staff led an Inter-agency Animal Models for Botulism Working Group.
  • NIAID staff participated in the Department of Homeland Security (DHS) Bioshield Scenarios Workshop: Botulinum Toxin. This workshop supported DHS efforts to develop requirements for medical countermeasures for this toxin.
  • NIAID established an Inter-agency Agreement with the DoD Armed Forces Research Institute of Medical Sciences (AFRIMS) site in Thailand to develop animal models of shigellosis, test shigella and other enteric vaccines in phase I trials, and gather data on endemic plague.
  • NIAID is participating in the FBI-sponsored Scientific Working Group on Microbial Genetics and Forensics. Other participants include Federal agency officials and scientists with expertise in genomics, bioinformatics, microbiology, and infectious diseases. The working group’s mission is to define criteria and coordinate the development and validation of microbial forensic methods that will support criminal investigations.


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Last Reviewed: July 22, 2005